Project Summary: Currently, there is a need for strategies that mitigate acute radiation-induced gastrointestinal syndrome (RIGS). The risk of large populations encountering radiation exposure is real and growing. Although a few drugs are available which can protect radiation injury if applied prior to radiation exposure, to date there are no agents available which can be applied 24 hr post-exposure to mitigate the acute radiation syndrome. The high radiosensitivity of the intestinal epithelium increases susceptibility to RIGS; and with mortality within 10-15 days there is limited time for therapeutic intervention. We have developed a human peripheral blood mono nuclear cell derived macrophage committed progenitor (MCP) cell therapy which can mitigate RIGS and improve survival when applied 24 hr after an otherwise lethal dose of radiation exposure. These progenitor cells are modulated ex-vivo to increase expression of WNT ligand, a major paracrine signal for intestinal epithelial regeneration. In this project we will fully characterize this novel cell therapy with a determination of an optimum dose and schedule for mitigation of RIGS. We will examine the general applicability of this strategy in young and radiosensitive animals. Finally we will evaluate the involvement of MCP derived WNT signaling in repair and regeneration of intestinal stem cells.